The broad long-term objectives of this proposal are two -fold:.(l) to elucidate novel endogenous pathways for anti-inflammatory lipid mediators (LM) and 2) assess their contributions to human health and disease. Oxidized lipids that act on human neutrophil (PMN) are generally considered as "proinflammatory mediators." In this project, the investigator found that certain mediators such as lipoxins (LX) possess down-regulatory actions in key events in inflammation and reperfusion injury. Aspirin (ASA) treatment actually trigger formation l5 epimeric lipoxins (ATL) that may underlie some of ASA's beneficial effects in vascular disease and cancer by pirating LX signaling.: In work in progress, the investigator found that ASA also triggers two novel pathways from eicosapentanoic acid (EPA, a major fish oil). Since ASA and dietary supplements of EPA are widely used in the U.S., it is important to elucidate anti-inflammatory factions on PMN. The investigator proposes the following novel hypothesis: Aspirin pirates function of natural counterregulatory lipid mediators during PMN interactions with inflamed and hypoxic endothelial cells. These local mediators mimic native LX at their PMN receptors, and other new compounds the investigator isolated antagonize proinflammatory leucotriene receptors. They down -regulate PMN and mimic navel endogenous "anti-inflammatory" lipid mediated circuits. To test this, four specific aims are proposed: Aim 1 will elucidate the novel aspirin-triggered lipid mediators (ATLM) derived from EPA :during endothelial-PMN interactions and their routes of formation. A second series examines formation by hypoxic cells. The ability of ATLM to block PMN will be established and ranked. Aim 2 addresses the recognition of novel ATLM and IX stable analogs by LXA4 and 1eucotriene B4 (LTB4) receptors using recombinant as well as receptor chimeras to determine mimetic/antagonist properties, and Aim 3 focuses on activation of these receptors by ATLM and other novel ligands. Aim 4 will focus on the impact of ATLM in inflammation and repefusion injury using transgenic mice overexpressing LXA4 receptors or LTB4 receptors to determine whether these circuits are responsible for the anti-inflammation. ATLM generation will be examined in these mice given EPA and ASA treatment. Completion of these aims will provide a new paradigm to address inflammatory diseases, namely by elucidating endogenous lipid mediators of anti-inflammation.